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FDA Approves First PARP Inhibitor with Myriad's BRACAnalysis as CDx in Advanced Ovarian Cancer

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NEW YORK (GenomeWeb) – The US Food and Drug Administration last week approved the first PARP inhibitor, AstraZeneca's Lynparza (olaparib), as a treatment for advanced ovarian cancer patients who have BRCA mutated tumors.

"The observed response rate of 34 percent in the patients with germline BRCA mutation-associated ovarian cancer who have received three lines of chemotherapy is better than what would be expected of available therapy and represents an improvement on a surrogate endpoint that is reasonably likely to predict clinical benefit," the FDA said in review documents.

Alongside the drug, the agency approved Myriad Genetics' BRACAnalysis test as a companion diagnostic to identify germline BRCA mutations in ovarian cancer patients considering treatment with Lynparza. For Myriad, its first FDA-approved companion test is a key milestone that the company has been working toward. More than a year ago, Myriad announced plans to use BRACAnalysis largely as a tool to identify best responders to PARP inhibitors and DNA-damaging agents, and move customers onto next-generation sequencing tests to assess people's risk of hereditary cancers.

"Less than 25 percent of ovarian cancer patients know their germline BRCA status," Mark Capone, president of Myriad Genetic Laboratories, said in a statement. This knowledge "is critical for any ovarian cancer patient who may be considered for treatment with Lynparza," he added.

The companion diagnostic testing will be performed in Myriad's lab in Salt Lake City, Utah. Last year, Myriad announced it would build a new laboratory at its Salt Lake City facility within which the company will develop companion diagnostics in line with FDA regulations. The new lab build out, Myriad said, expanded its existing non-exclusive deal with AstraZeneca to use BRACAnalysis in Lynparza trials.

Although Myriad has launched a tumor BRACAnalysis test in Europe that can gauge BRCA mutations in tissue samples, AstraZeneca did not respond to a question regarding whether it planned to eventually support the launch of such a test in the US as a companion diagnostic for Lynparza. The drug will be marketed in the US only with the germline BRACAnalysis test. According to Myriad's own research, the Tumor BRACAnalysis CDx can pick up 44 percent more deleterious markers in ovarian cancer patients than the germline test.

Myriad said it planned to continue to educate oncologists about the need for BRCA testing before prescribing Lynparza, but did not elaborate. An AstraZeneca spokesperson told GenomeWeb that "based on the small patient population for whom [the drug] is approved, the product will bedispensed exclusively through the pharmacy business unit of Biologics, Inc., an integratedoncology management company." AstraZeneca's existing sales force will provide support for commercializing the drug.

With Lynparza's approval, AstraZeneca has become the first drug developer to commercialize a PARP inhibitor. The drugmaker wouldn't disclose the price of the drug, but has estimated that it could eventually bring in as much as $2 billion in annual sales. The list price for BRACAnalysis is $4,040, but the cost will likely be significantly less for patients with insurance coverage. Both AstraZeneca and Myriad offer patients assistance programs to help them with the cost of treatments and tests.

"We are confident — based on our conversations with third-party payorsto date — that Lynparza will be covered by most commercial insurers," a company spokesperson said in an email to GenomeWeb.

Efficacy data

The FDA-approved label for the drug indicates Lynparza for the treatment of "patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy." According to review documents posted by the FDA, AstraZeneca had initially sought approval for Lynparza for the maintenance treatment of adults with platinum-sensitive relapsed ovarian cancer with germline BRCA mutations.

However, after members of the Oncologic Drugs Advisory Committee (ODAC) in June recommended by a majority vote that the FDA hold off granting accelerated approval to Lynparza until overall survival data were available, AstraZeneca supplied additional information to try to convince the agency that the risk/benefit profile of the drug still warranted accelerated approval in a non-maintenance setting – a population that lacks treatment options.

At the time of the ODAC hearing, AstraZeneca presented data from Study 19 to support Lynparza's approval in the platinum-sensitive maintenance setting. However, FDA reviewers raised concerns that the germline BRCA-mutated subgroup weren't randomized, they questioned whether the drug extended overall survival, and they worried about the adverse events the drug caused, mainly myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

In the overall ovarian cancer population in Study 19, Lynparza extended progression-free survival by a median of 8.4 months, compared to 4.8 months for those on placebo, but there wasn't a significant difference in overall survival. A preplanned subgroup analysis showed a subset of patients with BRCA mutations may garner more benefit from the PARP inhibitor, so researchers retrospectively identified patients for their BRCA status.

In this sub-population, progression-free survival was 11.2 months for those receiving Lynparza compared to 4.1 months for those on placebo. But overall survival was similar between patients with germline BRCA mutations and those with normal BRCA status.

Following ODAC's negative reception of this trial, AstraZeneca submitted data to the FDA from a single-arm trial, Study 42, which included 137 ovarian cancer patients with three or more lines of prior chemo, and with measurable germline BRCA mutations. Nearly all patients were treated with carboplatin; 46 had gotten cisplatin; and a majority had also received paclitaxel, doxorubicin, and gemcitabine. Studies have shown that patients with BRCA mutations also respond better to plantinum-based drugs than those without such mutations.

In Study 42, 34 percent of patients had an objective response to Lynparza, of which only 2 percent had a complete response. These responses lasted for an average of 7.9 months.

Weighing safety

Meanwhile, the safety of the drug was established based on 300 patients with germline BRCA-mutated ovarian cancer. The most common adverse events associated with Lynparza seen in trials were usually mild to moderate nausea, vomiting, fatigue, and anemia.

Out of 223 of these patients who had received three or more lines of prior chemo, eight died from adverse events – two patients had acute leukemia, and others had COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture.

The incidence of MDS or AML in Study 42 was 3.1 percent out of 193 ovarian cancer patients. In Study 19, the incidence was 2.2 percent. In a Lynparza safety database, the incidence was .8 percent. The FDA notes in its review documents that these rates are higher than the estimated annual incidence of MDS in the US of approximately 3.3 cases per 100,000, or .0033 percent.

One of the reviewers of AstraZeneca's data, Todd Palmby, noted that Lynparza's mechanism of action might "translate into an increased risk of developing secondary malignancies in patients treated with it" and that this risk might be "further increased in patients" with BRCA mutations.

BRCA genes are involved in repairing DNA damage in cells, a function essential to cell survival. However, when patients have mutations in BRCA1 and BRCA2 genes, cells in their body lose this repair ability. Although patients with BRCA1/2 mutations have a higher predisposition for breast and ovarian cancer, research suggests that they are also more likely to respond to the PARP inhibitor class of drugs. PARP inhibitors block cells' ability to repair DNA damage, so in BRCA-mutated tumors that are already DNA-repair deficient, the cancer cells are inundated with faulty DNA and die.

"[Lynparza's] anti-tumor activity and its potential activity to induce secondary malignancies may be through the same mechanism," according to Palmby's review of the data.

Still, in balancing these risks with the potential benefits in this advanced ovarian cancer population, the FDA decided to grant accelerated approval. "The serious risk of MDS/AML is considered acceptable considering the poor therapeutic options available to this population," the FDA explained in review documents. "This risk is mitigated by the use of this drug in selected patients (with germline BRCA mutation) who based on the mechanism of action are more likely to respond to olaparib."

In granting accelerated approval to Lynparza, FDA is also asking AstraZeneca to submit additional Phase III data to confirm the drug's clinical benefit. In particular, the company will have to submit final progression-free and overall survival data from an ongoing randomized, blinded trial (SOLO-2) investigating the efficacy of Lynparza as a maintenance therapy in relapsed, high-grade serous ovarian cancer or endometrioid cancer patients with BRCA mutations who have responded after platinum-based chemo.

AstraZeneca also must submit data from the SOLO-3 study gauging whether Lynparza is superior to a chemotherapy of a doctor's choosing in platinum-sensitive relapsed ovarian cancer patients with BRCA mutations. Data from SOLO-2 is slated to be reported next year, while SOLO-3 is expected to release data in 2019.

The drugmaker also must collect and analyze all cases of MDS or AML and submit a report to the agency annually for five years "to provide a more accurate assessment and understanding of the risk of this condition."

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